STEREOCHEMICALLY ENRICHED COMPOSITIONS FOR DELIVERY OF NUCLEIC ACIDS
Provided, in part, is a composition comprising one or more chemical entities of formula I, each of which is a compound of formula I: a pharmaceutically acceptable salt thereof, a solvate thereof, or a solvate of a pharmaceutically acceptable salt thereof, the composition characterized in that greater than a first threshold amount of the total amount of chemical entities of formula I in the composition: are chemical entities of formula I.a, wherein the first threshold amount is 50%; or are chemical entities of formula I.b.1, wherein the first threshold amount is 25%; or are chemical entities of formula I.b.2, wherein the first threshold amount is 25%, wherein the chemical entities of formula I.a, I.b.1, and I.b.2, are described herein, and methods of using such compositions, for example, for the delivery of a polynucleotide in vivo.
1 . A pharmaceutical composition comprising a lipid nanoparticle and a pharmaceutically acceptable excipient, wherein
the lipid nanoparticle comprises:
a polynucleotide that is messenger RNA (mRNA);
one or more non-cationic lipids that are not a cholesterol-based lipid, one or more cholesterol-based lipids and/or one or more PEG-modified lipids;
and
one or more chemical entities of formula I, each of which is a compound of formula I:
or
a pharmaceutically acceptable salt thereof
wherein 70% or more of the chemical entities of formula I have the structure set forth by formula I.a.i,
2 .- 7 . (canceled)
8 . The pharmaceutical composition of claim 1 , wherein 80% or more of the chemical entities of formula I have the structure set forth by formula I.a.i.
9 . The pharmaceutical composition of claim 1 , wherein 90% or more of the chemical entities of formula I have the structure set forth by formula I.a.i.
10 . The pharmaceutical composition of claim 1 , wherein 95% or more of the chemical entities of formula I have the structure set forth by formula I.a.i.
11 .- 47 . (canceled)
48 . A method of delivery of messenger RNA (mRNA) in vivo, comprising
administering to a subject in need of delivery the pharmaceutical composition of claim 1 , wherein administering of the lipid nanoparticle results in the expression of the therapeutic protein encoded by the mRNA in vivo.
49 .- 60 . (canceled)
61 . A method of treating a disease or disorder comprising the step of delivering an mRNA encoding a therapeutic protein using the pharmaceutical composition of claim 1 .
62 . The pharmaceutical composition of claim 1 , wherein the mRNA is unmodified.
63 . The pharmaceutical composition of claim 1 , wherein the mRNA comprises one or more modified nucleotides.
64 . The pharmaceutical composition of claim 63 , wherein the one or more modified nucleotides comprise pseudouridine, N-1-methyl-pseudouridine, 2-aminoadenosine, 2-thiothymidine, inosine, pyrrolo-pyrimidine, 3-methyl adenosine, 5-methylcytidine, 2-aminoadenosine, C5-bromouridine, C5-fluorouridine, C5-iodouridine, C5-propynyl-uridine, C5-propynyl-cytidine, C5-methylcytidine, 2-aminoadenosine, 7-deazaadenosine, 7-deaza-guanosine, 8-oxoadenosine, 8-oxoguanosine, O(6)-methylguanine, and/or 2-thiocytidine.
65 . The pharmaceutical composition of claim 1 , wherein the mRNA encodes a therapeutic protein.
66 . The pharmaceutical composition of claim 1 , wherein the pharmaceutical formulation is for oral, rectal, vaginal, transmucosal, pulmonary, or parenteral administration.
67 . The pharmaceutical composition of claim 66 , wherein the pulmonary administration is intratracheal or intestinal administration.
68 . The pharmaceutical composition of claim 66 , wherein the parenteral administration is intradermal, transdermal, intramuscular, subcutaneous, intramedullary, intrathecal, direct intraventricular, intravenous, intraperitoneal, or intranasal administration.
69 . The pharmaceutical composition of claim 65 , wherein the one or more non-cationic lipids are selected from the group consisting of DSPC (1,2-distearoyl-sn-glycero-3-phosphocholine), DPPC (1,2-dipalmitoyl-sn-glycero-3-phosphocholine), DOPE (1,2-dioleyl-sn-glycero-3-phosphoethanolamine), DOPC (1,2-dioleyl-sn-glycero-3-phosphotidylcholine), DPPE (1,2-dipalmitoyl-sn-glycero-3-phosphoethanolamine), DMPE (1,2-dimyristoyl-sn-glycero-3-phosphoethanolamine), and DOPG (1,2-dioleoyl-sn-glycero-3-phospho-(l′-rac-glycerol)).
70 . The pharmaceutical composition of claim 65 , wherein the one or more cholesterol-based lipids are cholesterol and/or PEGylated cholesterol.
71 . The pharmaceutical composition of claim 65 , wherein the one or more PEG-modified lipids comprise a poly(ethylene) glycol chain of up to 5 kDa covalently attached to a lipid with alkyl chain(s) of C6-C20 length.
72 . A method of delivery of messenger RNA (mRNA) in vivo, comprising administering to a subject in need of delivery the pharmaceutical composition of claim 69 , wherein administering of the lipid nanoparticle results in the expression of the therapeutic protein encoded by the mRNA in vivo.
73 . A method of delivery of messenger RNA (mRNA) in vivo, comprising administering to a subject in need of delivery the pharmaceutical composition of claim 70 , wherein administering of the lipid nanoparticle results in the expression of the therapeutic protein encoded by the mRNA in vivo.
74 . A method of delivery of messenger RNA (mRNA) in vivo, comprising administering to a subject in need of delivery the pharmaceutical composition of claim 71 , wherein administering of the lipid nanoparticle results in the expression of the therapeutic protein encoded by the mRNA in vivo.